It is well known that p75 knockout (p75KO) mice exhibit reduced heat sensitivity. This phenotype has been mainly attributed to a ~50% loss of sensory neurons from the dorsal root ganglia (DRG) during development, which was supported by a 2-3 fold decrease in NGF sensitivity of p75KO sensory neurons, when they are cultured in isolation without Schwann cells (SC). Besides having an effect on cell survival, p75 also had an impact on functionality of defined sensory subtypes, wherein the loss of p75 reduced the mechanical responsiveness of C-fibers and D-hair receptors as well as the heat sensitivity of A-fiber nociceptors in in vitro skin-nerve preparations. Surprisingly, our preliminary data from conditional p75 knockout mice illustrate that p75 influences nociception through its role in SC rather than from sensory neurons. These unexpected results are reminiscent of a report that demonstrated nociceptive defects due to a loss of sensory neurons, upon blocking ErbB receptor signaling or FGF receptor signaling in non-myelinating SC. Indeed, our preliminary data illustrate that there exists crosstalk between p75 and ErbB2 in response to BDNF in SC. Thus, we propose to investigate the role that p75 plays in nociception, using conditional knockout mice in which p75 is selectively deleted in SC or sensory neurons.